BACKGROUND An association between neuroinflammation, reduced adult neurogenesis, and cognitive impairment has been established in sleep deprivation (SD). Complement receptors are expressed on neuronal and glial cells, thus, regulate the neuroinflammation, neurogenesis and learning/memory. However, understanding of the effect of SD on the brain-immune system interaction associated with cognitive dysfunction and its mechanisms is obscure. We hypothesized that complement activation induced changes in inflammatory and neurogenesis related proteins might be involved in the cognitive impairment during SD. METHODOLOGY Adult male Sprague Dawley rats were used. Rats were sleep deprived for 48h using a novel automated SD apparatus. Dosage of BrdU (50mg/kg/day, i.p. in 0.07N NaOH), complement C3a receptor antagonist (C3aRA; SB290157; 1mg/kg/day, i.p.) in 1.16% v/v PBS and complement C5a receptor antagonist (C5aRA; W-54011; 1mg/kg/day, i.p.) in normal saline were used. Rats were subjected to spatial memory evaluation following SD. Hippocampal tissue was collected for biochemical, molecular, and immunohistochemical studies. T-test and ANOVA were used for the statistical analysis. RESULTS An up-regulation in the levels of complement components (C3, C5, C3a, C5a) and receptors (C3aR and C5aR) in hippocampus, displayed the complement activation during SD. Selective antagonism of C3aR/C5aR improved the spatial memory performance of sleep-deprived rats. C3aR antagonist (C3aRA) or C5aR antagonist (C5aRA) treatment inhibited the gliosis, maintained inflammatory cytokines balance in hippocampus during SD. Complement C3aR/C5aR antagonism improved hippocampal adult neurogenesis via up-regulating the BDNF level following SD. Administration of C3aRA and C5aRA significantly maintained synaptic homeostasis in hippocampus after SD. Gene expression analysis showed down-regulation in the mRNA levels of signal transduction pathways (Notch and Wnt), differentiation and axogenous proteins, which were found to be improved after C3aRA/C5aRA treatment. These findings were validated at protein and cellular level. Changes in the corticosterone level and ATP-adenosine-NO pathway were established as the key mechanisms underlying complement activation mediated consequences of SD. CONCLUSION Our study suggests complement (C3a-C3aR and C5a-C5aR) activation as the novel mechanism underlying spatial memory impairment via promoting neuroinflammation and adult neurogenesis decline in hippocampus during SD, thereby, complement (C3aR/C5aR) antagonist may serve as the novel therapeutics to improve the SD mediated consequences.

中文翻译：

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睡眠剥夺后，补体激活维持神经炎症并恶化大鼠海马的成年神经发生和空间记忆障碍

背景 已在睡眠剥夺 (SD) 中建立了神经炎症、成人神经发生减少和认知障碍之间的关联。补体受体在神经元和神经胶质细胞上表达，从而调节神经炎症、神经发生和学习/记忆。然而，对 SD 对与认知功能障碍相关的脑-免疫系统相互作用的影响及其机制的理解尚不清楚。我们假设补体激活诱导的炎症和神经发生相关蛋白的变化可能与 SD 期间的认知障碍有关。方法学使用成年雄性Sprague Dawley大鼠。使用新型自动化 SD 装置使大鼠睡眠不足 48 小时。BrdU（50mg/kg/天，在 0.07N NaOH 中 ip）、补体 C3a 受体拮抗剂（C3aRA；SB290157；1mg/kg/天，ip）在 1 中的剂量。使用生理盐水中的 16% v/v PBS 和补体 C5a 受体拮抗剂（C5aRA；W-54011；1mg/kg/天，ip）。SD后对大鼠进行空间记忆评估。收集海马组织用于生化、分子和免疫组织化学研究。T检验和方差分析用于统计分析。结果 海马中补体成分（C3、C5、C3a、C5a）和受体（C3aR 和 C5aR）水平的上调表明 SD 期间补体激活。C3aR/C5aR 的选择性拮抗改善了睡眠剥夺大鼠的空间记忆性能。C3aR 拮抗剂 (C3aRA) 或 C5aR 拮抗剂 (C5aRA) 治疗抑制神经胶质增生，维持 SD 期间海马中炎性细胞因子的平衡。补体 C3aR/C5aR 拮抗作用通过在 SD 后上调 BDNF 水平来改善海马成人神经发生。C3aRA 和 C5aRA 的给药显着维持了 SD 后海马的突触稳态。基因表达分析显示信号转导通路（Notch 和 Wnt）、分化和轴源蛋白的 mRNA 水平下调，发现在 C3aRA/C5aRA 治疗后得到改善。这些发现在蛋白质和细胞水平上得到了验证。皮质酮水平和 ATP-腺苷-NO 通路的变化被确定为补体激活介导 SD 后果的关键机制。